Iron composition for treating anemia

ABSTRACT

A method for treating hypoferric anemia in sucking mammals, said method comprising administering orally to a sucking mammal afflicted with hypoferric anemia a trivalent iron compound prepared by forming ferric oxide from soluble ferric iron salts by reaction with a member selected from the group consisting of Na2CO3, K2CO3, (NH4)2CO3, NaOH, KOH and NH4OH, preparing a mixture of this ferric oxide with at least one saccharide and a hexitol, neutralizing said mixture to a pH of between 6 and 9 by the addition of a hydroxycarboxylic acid, and concentrating the solution thus obtained to an iron concentration of about 80-150 mg/cc, and composition for achieving same.

United States Patent Taya IRON COMPOSITION FOR TREATING ANEMIA [76]Inventor: Miguel Margarit Taya, Manuel Girona 56, Barcelona, Spain [22]Filed: May 6, 1971 [2i] Appl. No: 140,995

Related US. Application Data [63] Continuation-impart of Ser. No.855,762, Sept. 5,

1969, abandoned.

[30] Foreign ApplicationPriority Data Nov. 20, 1968 Spain 360433 [52]US. Cl. 424/147, 424/180 [51] Int. Cl A6lk 27/00 [58] Field of Search424/147, 180, 176

[56] References Cited UNITED STATES PATENTS Lindvall et a] 424/1763,592,889 7/l97l Lindvall et al 424/l 47 Primary Examiner-Sam RosenAttorney, Agent, or FirmSughrue, Rothwell, Mion, Zinn & Macpeak [5 7ABSTRACT A method for treating hypoferric anemia in sucking mammals,said method comprising administering orally to a sucking mammalafflicted with hypoferric anemia a trivalent iron compound prepared byforming ferric oxide from soluble ferric iron salts by reaction vvith amember selected from the group consisting 14 Claims, No Drawings IRONCOMPOSITION FOR TREATING ANEMIA CROSS-REFERENCES TO RELATED APPLICATIONSThe present application is a continuation-in-part of U. S. applicationSer. No. 855,762, filed Sept. 5, 1969, now abandoned.

BACKGROUND OF THE INVENTION 1. Field of the Invention This inventionrelates to a process for the manufacture of a trivalent iron compoundsuitable for oral administration with a view to obtaining acceptableassimilable iron when administered by The above-mentioned way forveterinary purposes, suitable for combatting hypoferric anemias.

2. Description of the Prior Art The chemical literature contains adescription of the mainly comprising a mixture of saccharose and glucoseand later neutralized to a suitable pH of about 7.

In view of their stability and harmlessness, this combination is usedfor intravenous administration in anemic patients, the ironconcentration being about 2 to 5 percent. When attempting to achievehigher concentrations for animal therapy, the viscosity of thepreparation is increased extraordinarily, thus preventing success. Also,when attempting to concentrate, the metallic taste of these complexesrenders them unpleasant for oral administration.

The above-mentioned techniques are based on the preparation offerricoxide from soluble ferric salts, such as chloride, sulfate,citrate, etc., by reaction with sodium carbonate, wherebythe precipitateobtained may be washed sufficiently to remove the acid ion.

The ferric oxide obtained in the presence of a concentrated solution ofsaccharose and glucose, when heated in an alkaline medium, solubilizesto form a collodial solution, which already has a suitable pH or whichhas to be adjusted with an organic or mineral acid. Subsequentconcentration gives the desired iron content required; that is, around 2to 5 percent as has been indicated.

The presence of glucose partially converts the ferric ion into ferrousion and causes it to be included in the micelle of the colloidal ferricion. Accordingly, the product acquires a dark color and, what is moreimportant, a typical metallic taste. Because of its high viscosity, itis not possible to obtain iron concentrations'of around 80-15 mg Fe/cc,which are really suitable for oral administration, and more preferably100 mg/cc.

SUMMARY OF THE INVENTION It is, therefore, the main goal of the presentinvention to provide a process for obtaining a trivalent iron compoundsuitable for oral administration and easily assimilable by the digestivesystem of the animals to which it is to be administered withoutproducing disorders or lesions of any type in the organs of saiddigestive system.

The administration of a product orally to animals offers notableadvantages over the intramuscular or intravenous route, provided thatits absorption by the digestive system is assured and that it iscompletely harmless to the system. The possibility of oraladministration, mixed in with the food or drink supplied to animalsunder treatment, avoids the need for employing specialized personnel andthe difficulties inherent with parenteral administration.

Another object of the present invention is to provide a product obtainedby said process which will be readily absorbed in the intestines, atleast in the same amount as other known ferrous products are absorbed.

Accordingly, the process of the present invention resides in thepreparation of ferric oxide complexes with at least one saccharide bypartially or wholly substituting the glucose with a hexitol, such assorbitol and mannitol, whereby the reducing power of the sugar mixtureis extremely lowered, thus maintaining the ferric ion in such a state asto prevent the formation of ferrous ions. In an alternative embodiment,fructose may be substituted for the glucose employed.

In this manner, concentrations of around l50 mg Fe/cc and preferablymg/cc may be obtained with a viscosity of 6 to 10 centipoises at 25 C.In addition, the pH may be adjusted between 6 and 9 and still maintainproduct stability. This is accomplished by the addition of ahydroxycarboxylic acid, such as citric acid. This product lacks anymetallic taste and is perfectly tolerated gastrically. However, in viewof its concentration, it is not suitable for parenteral administration.

The product obtained in this manner may be readily dried, whereby a dryresidue of about 500 to 570 grams per liter of solution can be obtained.

The resulting product may be easily administered to animals sufferingfrom hypoferric anemia, at doses prescribed by the veterinarian, bearingin mind that the solution concentration should be around 80-150 mgFe/cc. This will be further discussed later in this application. Theproduct so formed finds special use in sucking mammals and sucking pigs.

Although sodium carbonate is the carbonate of choice to react with theiron salt, satisfactory results may be attained by employing othercarbonates as well, such as potassium and ammonium. In addition,excellent results have been achieved when sodium, potassium or ammoniumhydroxide is employed in place of the carbonate.

A better understanding of the present invention will be attained fromthe following examples, which are merely intended to be illustrative andnot limitative of the present invention.

- EXAMPLE] A suspension of ferric oxide (equivalent to 500 grams ofiron) is prepared from ferric chloride at a concentration of 200 mg ofiron/cc with sodium carbonate. The suspension is washed until thechlorine ion is completely eliminated. Once thisstage is reached, with avolume of about 20 liters, it is placed in a kettle with 1,300 grams ofsaccharose, 250 grams of 70 percent sorbitol and 50 grams of glucose.

i A solution of 100 grams of NaOH in about 400 cc of H 0 is added withstirring to the above mixture. The mixture is heated to reflux whereby ared liquid is obtained, which is concentrated down to 10 liters. Then asolution of 150 grams of citric acid in 250 cc of water is added to themixture. Finally the mixture is concentrated under vacuum to 5 liters,whereby a red liquid with a viscosity of 8 centipoises at 25 C and a pHof 6.5 is obtained, without any metallic taste. This may be convenientlyadministered orally in perfect condition for assimilation.

EXAMPLE II To a freshly prepared suspension of ferric oxide (equivalentto 500 grams of iron) is added 1.2 kg of saccharose and 500 grams of 70percent sorbitol together with l25 cc of a solution of 70 percent sodiumhydroxide. The mixture is refluxed with stirring and is concentrated,whereby a dark red solution is obtained, which is allowed to cool. Then150 grams of citric acid in solution is added and the mixture isconcentrated to 5 liters. A preservative is added and finally it isfiltered.

The product obtained is a colloidal dispersion of ferric hydroxide,anodic in an electrolytic solution.

This product exhibits a viscosity of between 6 and 9 centipoises(referred to water at 25 C), a dry residue of between 0.500 and 0.570gr/cc, pH between 6.5 and 9, and has no free ferrous or ferric ions.

The following tests described below have been performed to test thesafety of the products obtained on the gastric mucosa of animals thathave ingested them:

Test:

Five experimental batches were arranged, each comprising eight adultrats with an average weight of 200 grams each. They were administered adose of 500 mg Fe/kg body weight, with the maximum volume of liquidadministered being 2 cc/l gr body weight.

In all cases the Fe compound was administered orally by way of anesophagic probe. Previously, the weight of each rat was checked so as todetermine the dose.

The above-mentioned batches were differentiated by the iron compoundsadministered to each, as shown below:

The first batch of eight rats was administered ferrous gluconate.

The second batch of eight rats was administered ferrous sulfate.

The third batch of eight rats was administered ammoniacal iron citrate.

The fourth batch of eight rats was administered polysaccharide ironcomplex. I

The fifth batch of eight rats was not given any product.

The last batch of experimental animals was arranged as a control forcomparison of the results obtained in the other batches.

Four hours after administration of the abovementioned products, the ratswere sacrificed with an excess of anesthetic ether. They were examinedand the stomach was removed along with the first section of the duodenumto the continuous opening along the greater curvature.

The results obtained are as follows:

First batch: Clear inflammation and irritation from the limits of thepre-stomach and all along the greater curvature of the stomach.

Second batch: Congested surfaces all over the gastric mucosa withbleeding ulcerous areas.

Third batch: Congested areas with hemorrhages, especially on the greatercurvature; in the most affected cases, the congested area coveredone-third of the gland surface.

Fourth batch: No congestion was to be observed in the gastric mucosa.

Fifth batch (control batch): Normal pink color, free from congestion.

As is observed from the results obtained, the ferrous gluconate, theferrous sulfate and the ammoniacal ferrous citrate caused lesions in thegastric mucosa, while the poly-saccharide iron complex according to thepresent invention failed to exhibit any signs of gastric irritation.

Likewise, experiments have been performed with this product to test theintestinal absorption of the polysaccharideFe, in comparison with otheriron salts, for example, iron gluconate, the absorption efficiency ofwhich is well known.

The experimental method consisted of having an amount of iron ingestedand observing the sideraemia variations which occurred over severalhours afterwards. Thus, it is shown that, in principle, the greater thesideraemia, the greater the absorption. Accordingly, when the sideraemiais high, the absorption drops, since the transferrin (which is theplasma protein enabling iron transportation) has reached a state ofsaturation.

in addition, tests have been performed on large groups of sucking pigs,since hypoferric anemia is frequent in these animals. The ironabsorption was studied with the administration of ferrous gluconate to abatch of 22 sucking pigs and the polysaccharide complex to a secondbatch also comprising 22 animals. The dose administered was mg of ironper animal.

Sideraemic analyses were performed before administration of thepreparation, 3 hours and 8 hours after administration, with thenecessary amount of blood being removed from each animal.

The sideraemic results obtained were as follows:

With ferrous gluconate:

Time Mg Fe/lOO cc plasma 0 hr. 57.2 I 20.5 3 hrs. 712.0 1 33.4 8 hrs462.0 i 74.6

With the polysaccharide iron complex:

Time Mg/ Fe/lOO cc plasma 0 hr. 51 0 i 20 8 3 hrs. 610 0 i 50 6 8 hrs.480 O i 49 7 ily administered to sucking mammals without risk ofintestinal disorders and with complete assurance of excellentassimilation.

Insofar as the effective dosage rates of the product produced by thepresent invention is concerned, suitable results have been demonstratedwhen sucking mammals are administered a first dose of 1 cc 5 daysfollowing birth and subsequently administered a dose of 2 cc at 20 to 25days after birth. However, it is readily apparent to any skilledveterinarian, that dosage rates among animals varies. Accordingly, thedosage limitations indicated herein can be widely varied according tobody weight and severity of the hypoferric anemia.

Regarding the means-of dosage administration, extremely high success hasbeen encountered when oral administration is carried out by means of anaerosol dispersion. Aerosol devices capable of administering an allotteddosage of medicament are well known within the medical art. One of theseaerosol dispensing devices (sometimes called dosimeters) is theMagnimeter, which is produced by the Messrs. IDEV of France.

These dosimeters comprise a receptacle made from any suitable material,such as glass or aluminum. In addition to the receptacle, there isplaced within the receptacle means to produce the aerosol. Finally, thereceptacle is filled with a suitable amount of an inert carrier servingas a propellant and medicament in order that numerous doses may bedispensed. Particularly, excellent aerosol doses of high stability havebeen produced by employing nitrogen gas or butane gas as the propellant.Upon engaging the aerosol valve, a differential in pressure between thereceptacle pressure and the atmospheric pressure causes atomization orthe aerosol mist to form. While great success has been achieved with anitrogen and butane propellant, applicant does not wish to limit hisinvention to these alone. That is, any pharmaceutically acceptable inertcarrier capable of dispensing (in aerosol form) at least a 1 cc dose isacceptable, providing, however, stability of the product is notimpaired. As indicated above, excellent stability has been achieved withnitrogen and butane.

ln administering the dose of medication to a sucking 7 animal, theaerosol device containing the medicament osol device is engaged, thusreleasing a unit dose of v tered with a suitable eyedropper or othersuitable device capable of administering the solution.

Although the present invention has been adequately described in theforegoing specification and examples included therein, it is readilyapparent that various changes and modifications may be made withoutdeparting from the scope thereof.

What I claim is:

1. A pharmaceutical composition for oral administration useful in thetreatment of hypoferric anemia in sucking mammals, said compositioncomprising, in

combination, a pharmaceutically acceptable inert carrier and a trivalentiron compound prepared by:

1. forming ferric oxide, equivalent to 500 grams of iron, from solubleferric iron salts by reaction with a basic material selected from thegroup consisting of sodium carbonate, potassium carbonate, ammoniumcarbonate, sodium hydroxide, potassium hydroxide and ammonium hydroxide,

2. heating to reflux temperature, a mixture of the ferric oxide obtainedin (1) with from 1,200 to 1,300 grams of saccharose, 50 grams of amember selected from the group consisting of glucose and fructose, and250 grams of a percent hexitol solution, or optionally, heating toreflux temperature, a mixture of the ferric oxide obtained in 1) withfrom 1,200 to 1,300 grams of saccharose and 500 grams of a 70 percenthexitol solution,

said hexitol being a member selected from the group consisting ofsorbitol and mannitol,

3. neutralizing said mixture to a pH of between 6 and 9 by the additionof citric acid, and

' 4. concentrating the solution obtained to an iron con centration offrom about to 150 mg/cc.

2. The pharmaceutical composition of claim 1, wherein the ferric oxideis obtained from soluble ferric iron salts, selected from the groupconsisting of chloride, sulfate and citrate, by reaction with a memberselected from the group consisting of Na CO K CO (NH CO NaOH, KOH and NHOH and washing the precipitate obtained until the acid ion is completelyre moved.

3. The pharmaceutical composition of claim 1, wherein said compositionis in aerosol form and wherein the inert carrier is a member selectedfrom the group consisting of nitrogen and butane.

4. The pharmaceutical composition of claim 3, wherein the inert carrieris nitrogen.

5. The pharmaceutical composition of claim 3, wherein the inert carrieris butane.

6. The pharmaceutical composition of claim 1, wherein the concentrationof iron is about mg/cc.

7. A method for treating hyproferric anemia in sucking mammals, saidmethod comprising administering orally to a sucking mammal afflictedwith hypoferric anemia, an effective amount of a trivalent iron compoundprepared by:

l. forming ferric oxide, equivalent to 500 grams of iron, from solubleferric iron salts by reaction with a basic material selected from thegroup consisting of sodium carbonate, potassium carbonate, ammoniumcarbonate, sodium hydroxide, potassium hydroxide and ammonium hydroxide,

- 2. heating to reflux temperature, a mixture of the ferric oxideobtained in (l) with from 1,200 to 1,300 grams of saccharose, 50 gramsof a member selected from the group consisting of glucose and fructose,and 250 grams of a 70 percent hexitol solution, or optionally, heatingto reflux temperature, a mixture of the ferric oxide obtained in (1)with from 1,200 to 1,300 grams of saccharose and 500 grams of a 70percent hexitol solution, said hexitol being a member selected from thegroup consisting of sorbitol and mannitol,

3. neutralizing said mixture to a pH of between 6 and 9 by the additionof citric acid, and

4. concentrating the solution obtained to an iron concentration of fromabout 80 to 150 mg/cc.

8. The method of claim 7, wherein the trivalent iron compound isadministered in two doses, the first being administered in an amount of1 cc days after birth, and the second dose being administered in anamount of 2 cc, 20 to 25 days after birth.

9. The method of claim 7, wherein the ferric oxide is obtained fromsoluble ferric iron salts, selected from the group consisting ofchloride, sulfate and citrate, by reaction with a member selected fromthe group consisting of Na CO K CO (NH CO NaOl-l, KOH and NH OH,andwashing the precipitate obtained until the acid ion is completelyremoved.

tically acceptable inert carrier is butane.

2. heating to reflux temperaturE, a mixture of the ferric oxide obtainedin (1) with from 1,200 to 1,300 grams of saccharose, 50 grams of amember selected from the group consisting of glucose and fructose, and250 grams of a 70 percent hexitol solution, or optionally, heating toreflux temperature, a mixture of the ferric oxide obtained in (1) withfrom 1,200 to 1,300 grams of saccharose and 500 grams of a 70 percenthexitol solution, said hexitol being a member selected from the groupconsisting of sorbitol and mannitol,
 2. The pharmaceutical compositionof claim 1, wherein the ferric oxide is obtained from soluble ferriciron salts, selected from the group consisting of chloride, sulfate andcitrate, by reaction with a member selected from the group consisting ofNa2CO3, K2CO3, (NH4)2CO3, NaOH, KOH and NH4OH and washing theprecipitate obtained until the acid ion is completely removed. 2.heating to reflux temperature, a mixture of the ferric oxide obtained in(1) with from 1,200 to 1,300 grams of saccharose, 50 grams of a memberselected from the group consisting of glucose and fructose, and 250grams of a 70 percent hexitol solution, or optionally, heating to refluxtemperature, a mixture of the ferric oxide obtained in (1) with from1,200 to 1,300 grams of saccharose and 500 grams of a 70 percent hexitolsolution, said hexitol being a member selected from the group consistingof sorbitol and mannitol,
 3. The pharmaceutical composition of claim 1,wherein said composition is in aerosol form and wherein the inertcarrier is a member selected from the group consisting of nitrogen andbutane.
 3. neutralizing said mixture to a pH of between 6 and 9 by theaddition of citric acid, and
 3. neutralizing said mixture to a pH ofbetween 6 and 9 by the addition of citric acid, and
 4. concentrating thesolution obtained to an iron concentration of from about 80 to 150mg/cc.
 4. The pharmaceutical composition of claim 3, wherein the inertcarrier is nitrogen.
 4. concentrating the solution obtained to an ironconcentration of from about 80 to 150 mg/cc.
 5. The pharmaceuticalcomposition of claim 3, wherein the inert carrier is butane.
 6. Thepharmaceutical composition of claim 1, wherein the concentration of ironis about 100 mg/cc.
 7. A method for treating hyproferric anemia insucking mammals, said method comprising administering orally to asucking mammal afflicted with hypoferric anemia, an effective amount ofa trivalent iron compound prepared by:
 8. The method of claim 7, whereinthe trivalent iron compound is administered in two doses, the firstbeing administered in an amount of 1 cc 5 days after birth, and thesecond dose being administered in an amount of 2 cc, 20 to 25 days afterbirth.
 9. The method of claim 7, wherein the ferric oxide is obtainedfrom soluble ferric iron salts, selected from the group consisting ofchloride, sulfate and citrate, by reaction with a member selected fromthe group consisting of Na2CO3, K2CO3, (NH4)2CO3, NaOH, KOH and NH4OH,and washing the precipitate obtained until the acid ion is completelyremoved.
 10. The method of claim 7, further comprising, in combinationwith said trivalent iron compound, a pharmaceutically acceptable inertcarrier.
 11. The method of claim 7, wherein the final iron concentrationis about 100 mg/cc.
 12. The method of claim 10, wherein said trivalentiron compound and said pharmaceutically acceptable inert carrier arecontained in aerosol form, said inert carrier being a member selectedfrom the group consisting of nitrogen and butane.
 13. The method ofclaim 12, wherein the pharmaceutically acceptable inert carrier isnitrogen.
 14. The method of claim 12, wherein the pharmaceuticallyacceptable inert carrier is butane.